tbuckley/cabot-search huggingface dataset:
Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research
Authors: Xuhui Tong, Rong Tang, Mingming Xiao, Jin Xu, Wei Wang, Bo Zhang, Jiang Liu, Xianjun Yu, Si Shi
Journal: Journal of Hematology & Oncology (2022)

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.
Hydrogen Sulfide Creates a Favorable Immune Microenvironment for Colon Cancer
Authors: Taohua Yue, Jichang Li, Jing Zhu, Shuai Zuo, Xin Wang, Yucun Liu, Jia Liu, Xiaoyun Liu, Pengyuan Wang, Shanwen Chen
Journal: Cancer Research (2022)

Abstract Immunotherapy can elicit robust anticancer responses in the clinic. However, a large proportion of patients with colorectal cancer do not benefit from treatment. Although previous studies have shown that hydrogen sulfide (H2S) is involved in colorectal cancer development and immune escape, further insights into the mechanisms and related molecules are needed to identify approaches to reverse the tumor-supportive functions of H2S. Here, we observed significantly increased H2S levels in colorectal cancer tissues. Decreasing H2S levels by using CBS+/− mice or feeding mice a sulfur amino acid-restricted diet (SARD) led to a marked decrease in differentiated CD4+CD25+Foxp3+ Tregs and an increase in the CD8+ T-cell/Treg ratio. Endogenous or exogenous H2S depletion enhanced the efficacy of anti–PD-L1 and anti–CTLA4 treatment. H2S promoted Treg activation through the persulfidation of ENO1 at cysteine 119. Furthermore, H2S inhibited the migration of CD8+ T cells by increasing the expression of AAK-1 via ELK4 persulfidation at cysteine 25. Overall, reducing H2S levels engenders a favorable immune microenvironment in colorectal cancer by decreasing the persulfidation of ENO1 in Tregs and ELK4 in CD8+ T cells. SARD represents a potential dietary approach to promote responses to immunotherapies in colorectal cancer. Significance: H2S depletion increases the CD8+ T-cell/Treg ratio and enhances the efficacy of anti–PD-L1 and anti–CTLA4 treatment in colon cancer, identifying H2S as an anticancer immunotherapy target.
Epiregulin is a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis
Authors: Ian D. Odell, Holly Steach, Stephen B. Gauld, Lauren Reinke-Breen, Jozsef Karman, Tracy L. Carr, Joseph B. Wetter, Lucy Phillips, Monique Hinchcliff, Richard A. Flavell
Journal: Science Immunology (2022)

Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs. Here, we define a critical role of epiregulin-EGFR signaling between dendritic cells and fibroblasts to maintain elevated ECM production and accumulation in fibrotic tissue. We found that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon and that DC3-derived epiregulin activates EGFR on fibroblasts, driving a positive feedback loop through NOTCH signaling. In mouse models of skin and lung fibrosis, epiregulin was essential for persistence of fibrosis in both tissues, which could be abrogated by epiregulin genetic deficiency or a neutralizing antibody. Therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a previously unexplored biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and represents a promising antifibrotic target.
Tumor-promoting function and regulatory landscape of PD-L2 in B-cell lymphoma
Authors: Sumito Shingaki, Junji Koya, Mitsuhiro Yuasa, Yuki Saito, Mariko Tabata, Marni B. McClure, Seishi Ogawa, Kotoe Katayama, Yosuke Togashi, Seiya Imoto, Yasunori Kogure, Keisuke Kataoka
Journal: Leukemia (2022)
Racism, xenophobia, and discrimination: mapping pathways to health outcomes
Authors: Sujitha Selvarajah, Susanna Corona Maioli, Thilagawathi Abi Deivanayagam, Priscila de Morais Sato, Delan Devakumar, Seung-Sup Kim, Jonathan C Wells, Marcella Yoseph, Ibrahim Abubakar, Yin Paradies
Journal: The Lancet (2022)
Leukocyte telomere length in children born following blastocyst-stage embryo transfer
Authors: Cheng Wang, Yayun Gu, Jun Zhou, Jie Zang, Xiufeng Ling, Hong Li, Lingmin Hu, Bei Xu, Bo Zhang, Na Qin, Hong Lv, Weiwei Duan, Yue Jiang, Yuanlin He, Tao Jiang, Congcong Chen, Xiumei Han, Kun Zhou, Bo Xu, Xiaoyu Liu, Shiyao Tao, Yangqian Jiang, Jiangbo Du, Juncheng Dai, Feiyang Diao, Chuncheng Lu, Xuejiang Guo, Ran Huo, Jiayin Liu, Yuan Lin, Yankai Xia, Guangfu Jin, Hongxia Ma, Hongbing Shen, Zhibin Hu
Journal: Nature Medicine (2022)
Novel INHAT repressor drives glioblastoma growth by promoting ribosomal DNA transcription in glioma stem cells
Authors: Weiwei Tao, Hong Lei, Wenlong Luo, Zhi Huang, Peng Ling, Mengyue Guo, Lihao Wan, Kui Zhai, Qian Huang, Qiulian Wu, Shutong Xu, Liang Zeng, Xiuxing Wang, Zhiqiang Dong, Jeremy N Rich, Shideng Bao
Journal: Neuro-Oncology (2022)

Cancer cells including cancer stem cells exhibit a higher rate of ribosome biogenesis than normal cells to support rapid cell proliferation in tumors. However, the molecular mechanisms governing the preferential ribosome biogenesis in glioma stem cells (GSCs) remain unclear. In this work, we show that the novel INHAT repressor (NIR) promotes ribosomal DNA (rDNA) transcription to support GSC proliferation and glioblastoma (GBM) growth, suggesting that NIR is a potential therapeutic target for GBM.Immunoblotting, immunohistochemical and immunofluorescent analysis were used to determine NIR expression in GSCs and human GBMs. Using shRNA-mediated knockdown, we assessed the role and functional significance of NIR in GSCs and GSC-derived orthotopic GBM xenografts. We further performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which NIR promotes GBM progression.Our results show that high expression of NIR predicts poor survival in GBM patients. NIR is enriched in the nucleoli of GSCs in human GBMs. Disrupting NIR markedly suppresses GSC proliferation and tumor growth by inhibiting rDNA transcription and pre-ribosomal RNA synthesis. In mechanistic studies, we find that NIR activates rDNA transcription to promote GSC proliferation by cooperating with Nucleolin (NCL) and Nucleophosmin 1 (NPM1), 2 important nucleolar transcription factors.Our study uncovers a critical role of NIR-mediated rDNA transcription in the malignant progression of GBM, indicating that targeting this axis may provide a novel therapeutic strategy for GBM.
Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials
Authors: Olivia Pagani, Barbara A. Walley, Gini F. Fleming, Marco Colleoni, István Láng, Henry L. Gomez, Carlo Tondini, Harold J. Burstein, Matthew P. Goetz, Eva M. Ciruelos, Vered Stearns, Hervé R. Bonnefoi, Silvana Martino, Charles E. Geyer, Claudio Chini, Fabio Puglisi, Simon Spazzapan, Thomas Ruhstaller, Eric P. Winer, Barbara Ruepp, Sherene Loi, Alan S. Coates, Richard D. Gelber, Aron Goldhirsch, Meredith M. Regan, Prudence A. Francis
Journal: Journal of Clinical Oncology (2022)

JCO
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Association of the Tumor Microbiome with Genetic ProgramsIn order to understand the relationship between the presence of bacteria and cancer prognosis, Ghaddar and colleagues developed a single-cell analysis of host-microbiome interactions (SAHMI) computational pipeline to identify bacteria from single-cell RNA sequencing datasets from patients with pancreatic ductal adenocarcinomas (PDAC).They found that 0.6% of total reads could be attributed to microbial species.Using a series of controls to denoise potential contaminants and artifacts, the authors predicted that 0.01% of the reads were genuine intracellularassociated microbiota.Using barcodes from scRNA-seq for individual cells, they linked each bacterium to particular cell types.Bacterial reads were most strongly enriched in tumor cells themselves.Specific types of bacteria were associated with specific gene expression patterns, e.g., angiogenesis, differentiation, and metastasis.Tumors with greater bacterial loads exhibited increased fractions of activated T cells and natural killer cells.Finally, they showed that the presence of bacteria in tumors was associated with decreased survival across several cohorts of PDAC patients.Expert Commentary: A subset of pancreatic cancers harbors intracellular bacteria, associated with worse overall survival in patients.
Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance
Authors: Kai Fu, Fachao Xie, Fang Wang, Liwu Fu
Journal: Journal of Hematology & Oncology (2022)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.
Editor's Note: p38 Mitogen-Activated Protein Kinase-Driven MAPKAPK2 Regulates Invasion of Bladder Cancer by Modulation of MMP-2 and MMP-9 Activity
Authors: Binod Kumar, Sweaty Koul, Jane Petersen, Lakshmipathi Khandrika, Jeong S. Hwa, Randall B. Meacham, Shandra Wilson, Hari K. Koul
Journal: Cancer Research (2022)

The editors are publishing this note to alert readers to a concern about this article (1). Specifically, a portion of the image used in Fig. 2D representing invasion of HTB9 cells treated with anti–MMP-2 antibody was also used in Fig. 6B representing vector control (VC)-expressing HTB9 cells.
Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study
Authors: Khaled Shelbaya, Brian Claggett, Pranav Dorbala, Hicham Skali, Scott D. Solomon, Kunihiro Matsushita, Suma Konety, Thomas H. Mosley, Amil M. Shah
Journal: Circulation (2022)

Background: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. Methods: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011–2013) and 7 (2018–2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. Results: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1–7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. Conclusions: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.
A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia
Authors: Richard A. Voit, Liming Tao, Fulong Yu, Liam D. Cato, Blake Cohen, Travis J. Fleming, Mateusz Antoszewski, Xiaotian Liao, Claudia Fiorini, Satish K. Nandakumar, Lara Wahlster, Kristian Teichert, Aviv Regev, Vijay G. Sankaran
Journal: Nature Immunology (2022)

Abstract The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.
Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking
Authors: Bowen Tang, Qianwen Liu, Anna Ilar, Pernilla Wiebert, Sara Hägg, Leonid Padyukov, Lars Klareskog, Lars Alfredsson, Xia Jiang
Journal: Annals of the Rheumatic Diseases (2022)

To assess the effects of occupational inhalable exposures on rheumatoid arthritis (RA) development and their interactions with smoking and RA-risk genes, stratifying by presence of anticitrullinated protein antibodies (ACPA).Data came from the Swedish Epidemiological Investigation of RA, consisting of 4033 incident RA cases and 6485 matched controls. Occupational histories were retrieved, combining with a Swedish national job-exposure matrix, to estimate exposure to 32 inhalable agents. Genetic data were used to define Genetic Risk Score (GRS) or carrying any copy of human leucocyte antigen class II shared epitope (HLA-SE) alleles. Associations were identified with unconditional logistical regression models. Attributable proportion due to interaction was estimated to evaluate presence of interaction.Exposure to any occupational inhalable agents was associated with increased risk for ACPA-positive RA (OR 1.25, 95% CI 1.12 to 1.38). The risk increased as number of exposed agents increased (Ptrend<0.001) or duration of exposure elongated (Ptrend<0.001). When jointly considering exposure to any occupational inhalable agents, smoking and high GRS, a markedly elevated risk for ACPA-positive RA was observed among the triple-exposed group compared with those not exposed to any (OR 18.22, 95% CI 11.77 to 28.19). Significant interactions were found between occupational inhalable agents and smoking/genetic factors (high GRS or HLA-SE) in ACPA-positive RA.Occupational inhalable agents could act as important environmental triggers in RA development and interact with smoking and RA-risk genes leading to excessive risk for ACPA-positive RA. Future studies are warranted to assess preventive strategies aimed at reducing occupational hazards and smoking, especially among those who are genetically vulnerable.
Lifestyle factors for the prevention of inflammatory bowel disease
Authors: Emily W Lopes, Simon S M Chan, Mingyang Song, Jonas F Ludvigsson, Niclas Håkansson, Paul Lochhead, Allan Clark, Kristin E Burke, Ashwin N Ananthakrishnan, Amanda J Cross, Domenico Palli, Manuela M Bergmann, James M Richter, Andrew T Chan, Ola Olén, Alicja Wolk, Hamed Khalili
Journal: Gut (2022)

To estimate the proportion of cases of Crohn's disease (CD) and ulcerative colitis (UC) that could be prevented by modifiable lifestyle factors.
Axonal degeneration in the anterior insular cortex is associated with Alzheimer’s co-pathology in Parkinson’s disease and dementia with Lewy bodies
Authors: Yasmine Y. Fathy, Laura E. Jonkman, John J. Bol, Evelien Timmermans, Allert J. Jonker, Annemieke J. M. Rozemuller, Wilma D. J. van de Berg
Journal: Translational Neurodegeneration (2022)

Abstract Background Axons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB. Methods α-Synuclein, phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insular (agranular and dysgranular) subregions of post-mortem human brains ( n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy. Results Compared to PD and PDD, DLB showed significantly higher α-synuclein and p-tau pathology load, argyrophilic grains, and more severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significantly higher load of amyloid-β pathology and its axonal density correlated with cognitive performance. p-Tau contributed most to axonal loss in the DLB group, was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit. Conclusions Our results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies, leading to impaired axonal integrity in PD, PDD and DLB, disrupting their functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.
Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis
Authors: Lotte van Ouwerkerk, Maarten Boers, Paul Emery, Pascal HP de Jong, Robert BM Landewé, Willem Lems, Josef S Smolen, Patrick Verschueren, Tom WJ Huizinga, Cornelia F Allaart, Sytske Anne Bergstra
Journal: Annals of the Rheumatic Diseases (2022)

To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this.Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome.The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended.Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low.